Lane Steven W, Scadden David T, Gilliland D Gary
Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA.
Blood. 2009 Aug 6;114(6):1150-7. doi: 10.1182/blood-2009-01-202606. Epub 2009 Apr 28.
The genetic events that contribute to the pathogenesis of acute myeloid leukemia are among the best characterized of all human malignancies. However, with notable exceptions such as acute promyelocytic leukemia, significant improvements in outcome based on these insights have not been forthcoming. Acute myeloid leukemia is a paradigm of cancer stem (or leukemia initiating) cells with hierarchy analogous to that seen in hematopoiesis. Normal hematopoiesis requires complex bidirectional interactions between the bone marrow microenvironment (or niche) and hematopoietic stem cells (HSCs). These interactions are critical for the maintenance of normal HSC quiescence and perturbations can influence HSC self-renewal. Leukemia stem cells (LSCs), which also possess limitless self-renewal, may hijack these homeostatic mechanisms, take refuge within the sanctuary of the niche during chemotherapy, and consequently contribute to eventual disease relapse. We will discuss the emerging evidence supporting the importance of the bone marrow microenvironment in LSC survival and consider the physiologic interactions of HSCs and the niche that inform our understanding of microenvironment support of LSCs. Finally, we will discuss approaches for the rational development of therapies that target the microenvironment.
导致急性髓系白血病发病机制的遗传事件是所有人类恶性肿瘤中特征最为明确的。然而，除了急性早幼粒细胞白血病等显著例外情况外，基于这些认识所带来的预后显著改善尚未实现。急性髓系白血病是癌症干细胞（或白血病起始细胞）的范例，其具有类似于造血过程中所见的层级结构。正常造血需要骨髓微环境（或龛位）与造血干细胞（HSC）之间复杂的双向相互作用。这些相互作用对于维持正常HSC的静止状态至关重要，而干扰可能会影响HSC的自我更新。白血病干细胞（LSC）同样具有无限自我更新能力，它们可能会劫持这些稳态机制，在化疗期间藏身于龛位的庇护所内，从而导致最终的疾病复发。我们将讨论支持骨髓微环境在LSC存活中重要性的新证据，并考虑HSC与龛位的生理相互作用，这些相互作用有助于我们理解微环境对LSC的支持。最后，我们将讨论针对微环境进行合理治疗开发的方法。
